Pyrazolopyridines

ABSTRACT

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. §119 to U.S. Provisional Application No. 61/175,897, filed May 6, 2009 and entitled “PYRAZOLOPYRIDINES”, the entire contents of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell (see Hardie, G. and Hanks, S. The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.: 1995).

In general, protein kinases mediate intracellular signaling by affecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g. shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H₂O₂), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-a), and growth factors (e.g. granulocyte macrophage-colony stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, survival and regulation of the cell cycle.

Kinases may be categorized into families by the substrates they phosphorylate (e.g. protein-tyrosine, protein-serine/threonine, lipids etc). Sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576-596; Knighton et al., Science 1991, 253, 407-414; Hiles et al, Cell 1992, 70, 419-429; Kunz et al, Cell 1993, 73, 585-596; Garcia-Bustos et al, EMBO J. 1994, 13, 2352-2361).

A serine/threonine kinase, protein kinase C-theta (PKC-theta), is a member of the novel, calcium independent PKC subfamily that is selectively expressed in T cells and skeletal muscle. Several lines of evidence indicate that PKC-theta has an essential role in T cell activation. Upon antigen stimulation of T cells, PKC-theta, but not other PKC isoforms, rapidly translocates from the cytoplasm to the site of cell contact between the T cell and antigen-presenting cell (APC), where it localizes with the T cell receptor (TCR) in a region termed the central supramolecular activation cluster (cSMAC) (Monks et al., 1997, Nature, 385: 83-86; Monks et al., 1998, Nature, 395: 82-86).

It has been reported that PKC-theta selectively activates the transcription factors AP-1 and NF-κB and integrates TCR and CD28 co-stimulatory signals leading to the activation of the CD28 response element (CD28RE) in the IL-2 promotor (Baier-Bitterlich et al., 1996, Mol. Cell. Biol., 16: 1842-1850; Coudronniere et al., 2000, PNAS, 97: 3394-3399). The specific role for PKC-theta in CD3/CD28 co-stimulation of T cells is highlighted in a study where expression of a kinase-dead PKC-theta mutant, or anti-sense PKC-theta dose-dependently inhibited CD3/CD28 co-stimulated NF-κB activation, but not TNF-alpha-stimulated NF-κB activation. This was not seen with other PKC isoforms (Lin et al., 2000, Mol. Cell. Biol., 20: 2933-2940). Recruitment of PKC-theta to the SMAC is reported to be mediated by its N-terminal regulatory domain and is necessary for T cell activation, as an over-expressed PKC-theta catalytic fragment did not translocate and was unable to activate NF-κB, whereas a PKC-theta catalytic domain-Lck membrane-binding domain chimera was able to reconstitute signaling (Bi et al., 2001, Nat. Immunol., 2:556-563).

Translocation of PKC-theta to the SMAC appears to be mediated by a largely PLC-gamma/DAG-independent mechanism, involving Vav and PI3-kinase (Villalba et al., 2002, JCB 157: 253-263), whilst activation of PKC-theta requires input from several signaling components including Lck, ZAP-70, SLP-76, PLC-gamma, Vav and PI3-kinase (Liu et al., 2000, JBC, 275: 3606-3609; Herndon et al., 2001, J. Immunol., 166: 5654-5664; Dienz et al., 2002, J. Immunol., 169: 365-372; Bauer et al., 2001 JBC., 276: 31627-31634). These biochemical studies in human T cells have gained credence from studies in PKC-theta knockout mice, which have confirmed a crucial role for this enzyme in T cell function. PKC-theta−/− mice are healthy and fertile, have a normally developed immune system, but exhibit profound defects in mature T cell activation (Sun et al., 200, Nature, 404:402-407). Proliferative responses to TCR and TCR/CD28 co-stimulation were inhibited (>90%) as were in vivo responses to antigen. In agreement with studies on human T cells, activation of the transcription factors AP-1 and NF-κB was abrogated, resulting in a severe deficit in IL-2 production and IL-2 R upregulation (Baier-Bitterlich et al., 1996, MBC, 16, 1842; Lin et al., 2000, MCB, 20, 2933; Courdonniere, 2000, 97, 3394). More recently, studies in PKC-theta-deficient mice have indicated a role for PKC-theta in the development of mouse models of autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA) and irritable bowel disease (IBD) (Salek-Ardakani et al., 2006; Tan et al., 2006; Healy et al., 2006; Anderson et al., 2006). In these models, PKC-theta-deficient mice exhibited a marked reduction in disease severity that was associated with a profound defect in the development and effector function of autoreactive T cells.

In addition to its role in T cell activation, PKC-theta is reported to mediate the phorbol ester-triggered survival signal that protects T cells from Fas- and UV-induced apoptosis (Villalba et al., 2001, J. Immunol. 166: 5955-5963; Berttolotto et al., 2000, 275: 37246-37250). This pro-survival role is of interest because the human PKC-theta gene has been mapped to chromosome 10 (10p15), a region associated with mutations leading to T cell leukaemias and lymphomas (Erdel et al., 1995, Genomics 25: 295-297; Verma et al., 1987, J. Cancer Res. Clin. Oncol., 113: 192-196).

In vivo, the role for PKC-theta in immune responses to infection is dependent on the type of pathogen encountered. PKC-theta deficient mice elicit normal Th1 and cytotoxic T cell-mediated responses to several viral infections and the protozoan'parasite, Leishmania major and effectively clear these infections (Marsland et al., 2004; Berg-Brown et al., 2004; Marsland et al., 2005; Giannoni et al., 2005). However, PKC-theta deficient mice are unable to wage normal Th2 T cell responses against the parasite Nippostrongylus brasiliensis and certain allergens (Marsland et al., 2004; Salek-Ardakani et al., 2004) and are unable to clear Listeria monocytogenes infection (Sakowicz-Burkiewicz et al., 2008). Clearly in some circumstances, the requirement for PKC-theta in T cell activation can be bypassed and this is likely to involve the provision of additional signals to T cells, either from cells of the innate immune system, or directly from the pathogen in the form of pathogen associated molecular patterns (PAMPs) (Marsland et al., 2007).

More recently, studies in PKC-theta-deficient mice have indicated a role for PKC-theta in the development of mouse models of autoimmune diseases, including multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease. In all cases where examined, PKC-theta-deficient mice exhibited a marked reduction in disease severity that was associated with a profound defect in the development of a newly discovered class of T cells, Th17 cells (Salek-Ardakani et al., 2006; Tan et al., 2006; Healy et al., 2006; Anderson et al., 2006; Nagahama et al., 2008). PKC-theta therefore appears to be essential for the development of pathogenic auto-reactive Th17 cells in the context of autoimmunity. These observations support the notion that targeting PKC-theta will provide a way to target autoimmune T cell responses, leaving many T cell responses (e.g., to viral infections) intact.

In addition to its role in T cell activation, PKC-theta mediates the phorbol ester-triggered survival signal that protects T cells from Fas- and UV-induced apoptosis (Villalba et al., 2001, J. Immunol. 166: 5955-5963; Berttolotto et al., 2000, 275: 37246-37250). This pro-survival role is of interest because the human PKC-theta gene has been mapped to chromosome 10 (10p15), a region associated with mutations leading to T cell leukaemias and lymphomas (Erdel et al., 1995, Genomics 25: 295-297; Verma et al., 1987, J. Cancer Res. Clin. Oncol., 113: 192-196).

Together, these data indicate that PKC-theta is an attractive target for therapeutic intervention in inflammatory disorders, immune disorders, lymphomas and T cell leukaemias.

Accordingly, there is a great need to develop compounds useful as inhibitors of protein kinases. In particular, it would be desirable to develop compounds that are useful as inhibitors of kinases such as PKC-theta, particularly given the inadequate treatments currently available for the majority of the disorders implicated in their activation.

SUMMARY OF THE INVENTION

This invention provides, in general, compounds that are useful as kinase inhibitors.

In one embodiment the compounds of the present invention are represented by a structural formula I or IA:

or a pharmaceutically acceptable salt thereof.

Each ring A is independently a five membered heteroaromatic ring, optionally substituted with one or more R₁.

Ring B is five- or six-membered saturated carbocyclic or heterocyclic ring. Each R₁ is —H, halogen, —CN, —NO₂, or -T1-Q1.

T1 is absent or a C1-10 aliphatic wherein one or more methylene units of T1 are optionally and independently replaced by G wherein G is —O—, —S(O)_(P)—, —N(R′)—, or —C(O)—; and T1 is optionally and independently substituted with one or more J_(T1).

Q1 is absent or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, or an 8-12 membered saturated, partially saturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from the group consisting of O, N, and S, wherein Q1 is optionally and independently substituted with one or more J_(Q1); wherein when R₁ is T1-Q1, then T1 and Q1 are not both absent.

R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)C(O)N(R*)₂, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, —(CR⁺⁺ ₂)_(n)N(R*)C(O)R*, or C1-10 aliphatic optionally substituted with one or more halogen, or phenyl.

Each R₃ and R₄ independently are —H, halogen, C1-10 aliphatic, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl, wherein R₃ and R₄ are optionally and independently substituted with one or more selected from the group consisting of C1-10 alkyl, halogen, —CN, —NO₂, —N(R*)₂, —S(O)_(p)R*, —S(O)_(p)NR*, —C(O)N(R*)₂, —NR*C(O), —OC(O)N(R*)₂, —N(R*)C(O)OR*, —N(R*)C(O)N(R*)₂ and —OR*; or R₃ and R₄ taken together with the carbon to which they are attached form C═O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, ═N—R*, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —NO₂, —N(R*)₂, —S(O)_(p)R*, —S(O)_(p)NR*, —C(O)N(R*)₂, —NR*C(O), —OC(O)N(R*)₂, —N(R*)C(O)OR*, —N(R*)C(O)N(R*)₂ and —OR*.

Each R₅ and R₆ are independently —H, halogen, C1-10 haloaliphatic, or C1-10 aliphatic

Each R₇ is independently C1-10 haloaliphatic, C1-10 aliphatic, halogen, —NO₂, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)N(R**)₂, —(CR⁺⁺ ₂)_(n)OR* or —(CR⁺⁺ ₂)_(n)C(O)N(R**)₂, or two R₇ groups together with the carbon to which they are attached form C═O.

Each J_(T1) is independently halogen, —OR^(̂), —N(R^(̂))₂, or —CN.

Each J_(Q1) is independently halogen, C1-10 alkyl, C1-10 haloalkyl, —OR″, —N(R″)₂, —CN, —NO₂, —S(O)_(P)R″, —S(O)_(p)NR″, —C(O)N(R″)₂, —N(R″)C(O)R″, acyl, carbalkoxyalkyl, or acetoxyalkyl.

Each R⁺⁺ is independently —H or halogen.

Each R′ is independently —H or C1-10 alkyl optionally and independently substituted with up to five halogen groups.

Each R^(̂) is independently —H, C1-10 alkyl, or aralkyl wherein each R^(̂) is optionally and independently substituted with up to five halogen groups.

Each R″ is independently —H or C1-10 alkyl optionally and independently substituted with up to five halogen groups.

Each R* is independently —H or C1-10 alkyl or aralkyl optionally and independently substituted with up to five halogen groups.

Each R** is independently —H or C1-10 alkyl optionally and independently substituted with up to five halogen groups.

y is 0, 1 or 2.

Each n is independently 0, or 1-10.

Each p is independently 0, 1, or 2.

In one embodiment, the present invention is a method of treating or preventing protein kinase-mediated condition in a subject, comprising administering to the subject an effective amount of a compound or composition of the present invention.

In one embodiment the present invention is the manufacture of a compound or composition of the present invention for use in treating or preventing a protein kinase-mediated condition in a subject.

In another embodiment, the compounds and compositions of the present invention are also useful for the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to compounds and compositions (such as, pharmaceutical compositions) useful as protein kinase inhibitors.

In one embodiment, the compounds and compositions of the present invention are effective as inhibitors of PKCtheta.

Compounds of this invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

In a first embodiment the compounds of the present invention are represented by a structural formula I, and the remainder of the variables are as described above. In an alternative embodiment the compounds of the present invention are represented by a structural formula IA, and the remainder of the variables are as described above.

In a second embodiment for compounds represented by Formula I and IA, each R₁ is independently —H, halogen, or -T1-Q1, and the remainder of the variables are as described in the first embodiment.

In a third embodiment for compounds represented by Formula I and IA, T1 is absent or a C1-10 aliphatic wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —O—, —N(R′)—, or —C(O)—; and T1 is optionally and independently substituted with one or more J_(T1). Q1 is absent or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein Q1 is optionally and independently substituted with one or more J_(Q1) and the remainder of the variables are as described in the second embodiment.

In a fourth embodiment for compounds represented by Formula I and IA,

each J_(T1) is independently —OR^(̂), —N(R^(̂))₂, or —CN. each J_(Q1) is independently C1-10 alkyl, —OR″, —N(R″)₂, or acyl and the remainder of the variables are as described in the third embodiment.

In a fifth embodiment for compounds represented by Formula I, R₂, is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)C(O)N(R*)₂, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen. Each R₃ and R₄ independently is —H, C1-10 aliphatic, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl wherein R₃ and R₄ are optionally and independently substituted with one or more selected from the group consisting of halogen, —CN, —NO₂, —N(R*)₂, and —OR % or R₃ and R₄ taken together with the carbon to which they are attached form C═O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R)₂, and —OR* and the remainder of the variables are as described in the fourth embodiment.

In a sixth embodiment for compounds represented by Formula I, each R₃ and R₄ independently is —H, C1-10 aliphatic, cycloalkylalkyl, wherein R₃ and R₄ are optionally and independently substituted with one or more selected from the group consisting of halogen, —CN, —NO₂, —N(R*)₂, and —OR*; or R₃ and R₄ taken together with the carbon to which they are attached form C═O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)₂, and —OR* and the remainder of the variables are as described in the first embodiment.

In a seventh embodiment for compounds represented by Formula I and IA, J_(T1) is —OR^(̂) and the remainder of the variables are as described in the sixth embodiment.

In an eighth embodiment for compounds represented by Formula I, R₂, is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen and the remainder of the variables are as described in the seventh embodiment.

In a ninth embodiment for compounds represented by Formula I and IA, R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen. R₃ and R₄ taken together with the carbon to which they are attached form a 3-8 membered saturated, or partially saturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)₂, and —OR* and the remainder of the variables are as described in the eighth embodiment.

In a tenth embodiment for compounds represented by Formula I, R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen. R₃ and R₄ taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, imidazolinyl, thiazolidinyl, or oxazolidinyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)₂, and —OR* and the remainder of the variables are as described in the ninth embodiment.

In an eleventh embodiment for compounds represented by Formula I, R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen. R₃ and R₄ taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, imidazolinyl, thiazolidinyl, or oxazolidinyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)₂, and —OR* and the remainder of the variables are as described in the tenth embodiment.

In a twelfth embodiment for compounds represented by Formula I and IA, R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen. R₃ and R₄ taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, or cyclopentyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)₂, and —OR and the remainder of the variables are as described in the eleventh embodiment.

In a thirteenth embodiment for compounds represented by Formula I, R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen. Each R₃ and R₄ independently is —H, C1-10 aliphatic, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl wherein R₃ and R₄ are optionally and independently substituted with one or more selected from the group consisting of halogen, —CN, —NO₂, —N(R*)₂, and —OR* and the remainder of the variables are as described in the eighth embodiment.

In a fourteenth embodiment for compounds represented by Formula I and IA, R₅ is —H, Cl, C1-4 haloalkyl, or C1-4 alkyl. R₆ is —H or C1-4 alkyl and the remainder of the variables are as described in the twelfth and thirteenth embodiment.

In a fifteenth embodiment for compounds represented by Formula I and IA, R₅ is —H, Cl, trifluoromethyl, methyl, ethyl, or cyclopropyl. R₆ is —H and the remainder of the variables are as described in the fourteenth embodiment.

In a sixteenth embodiment for compounds represented by Formula I and IA, R₅ is trifluoromethyl. R₆ is —H and the remainder of the variables are as described in the fifteenth embodiment.

In a seventeenth embodiment for compounds represented by Formula IA, ring B is five- or six-membered saturated carbocyclic ring and the remainder of the variables are as described in the fourth embodiment.

In an eighteenth embodiment for compounds represented by Formula IA, each R₇ is independently C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R**)₂, or —OR″; or two R₇ groups together with the carbon to which they are attached form C═O and the remainder of the variables are as described in the seventeenth embodiment.

In a nineteenth embodiment for compounds represented by Formula IA, A is —C(R⁺)— and the remainder of the variables are as described in the eighteenth embodiment.

In a twentieth embodiment for compounds represented by Formula IA, J_(T1) is —OR^(̂) and the remainder of the variables are as described in the nineteenth embodiment.

In a twenty first embodiment for compounds represented by Formula IA, each J_(Q1) is independently C1-10 alkyl, —OR″, —N(R″)₂, or acyl and the remainder of the variables are as described in the twentieth embodiment.

In a twenty second embodiment for compounds represented by Formula IA, ring B is five-membered saturated carbocyclic ring and the remainder of the variables are as described in the twenty first embodiment.

As used herein “one or more” means, for example, that all substitutable carbon atoms can be substituted, for example, up to 6 carbons atoms, up to 5 carbon atoms, up to 3 carbon atoms, up to 2 carbon atoms, or one carbon atom can be substituted.

As described herein, a specified number range of atoms includes any integer therein. For example, a group having from 1-4 atoms could have 1, 2, 3, or 4 atoms.

As used here the terms “absent” and “a bond” can be used interchangeably to mean the variable does not exits in that embodiment, that is the variable does not represent an atom or groups of atoms.

The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, recovery, storage, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched), branched, or cyclic hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation but is non-aromatic. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In certain embodiments, aliphatic groups may be linear or branched. Unless indicated aliphatic groups include, but are not limited to, alkyl, alkenyl, or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, methenyl (═CH₂), ethenyl, n-butenyl, ethynyl, and tert-butyl. Specifically examples, include but are not limited to, for example, a C1-10 aliphatic substituted with C1-6 alkyl includes n-butylene substituted with cyclohexyl.

The term “alkyl” as used herein means a saturated straight, branched or cyclic hydrocarbon. The term “alkenyl” as used herein means a straight or branched chain hydrocarbon comprising one or more double bonds. The term “alkynyl” as used herein means a straight or branched chain hydrocarbon comprising one or more triple bonds. Unless otherwise specified, alkyl, alkenyl and alkynyl groups contain 1-20 carbon atoms. In some embodiments, alkyl, alkenyl and alkynyl groups contain 1-10 carbon atoms. In other embodiments, alkyl, alkenyl and alkynyl groups contain 1-8 carbon atoms. In still other embodiments, alkyl, alkenyl and alkynyl groups contain 1-6 carbon atoms, and in yet other embodiments alkyl, alkenyl and alkynyl groups contain 1-4 carbon atoms.

The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl” or “carbocyclic”) refers to a non-aromatic monocyclic or polycyclic carbon containing ring which can be saturated or contain one or more units of unsaturation, having three to fourteen ring carbon atoms. The term includes polycyclic fused, spiro or bridged carbocyclic ring systems wherein the radical or point of attachment is on the carbocyclic ring. The term also includes polycyclic ring systems in which the carbocyclic ring can be attached to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the carbocyclic ring. Fused bicyclic ring systems comprise two rings which share two adjoining ring atoms, bridged bicyclic group comprise two rings which share three or four adjacent ring atoms, Spiro bicyclic ring systems share one ring atom. Examples of cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Specific examples include, but are not limited to, cyclohexyl, cyclopropentyl, and cyclobutyl.

The term “heterocycle” (or “heterocyclyl”, or “heterocyclic”) as used herein means refers to a non-aromatic monocyclic or polycyclic ring which can be saturated or contain one or more units of unsaturation, having three to fourteen ring atoms in which one or more ring carbons is replaced by a heteroatom such as, N, S, or O. The term includes polycyclic fused, spiro or bridged heterocyclic ring systems wherein the radical or point of attachment is on the heterocyclic ring. The term also includes polycyclic ring systems in which the heterocyclic ring can be attached to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the heterocyclic ring. Examples of heterocycles include, but are not limited to, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azetidinylazocanyl, diazocanyl, triazocanyl, oxazolidinyl, oxetenyl, isoxazolidinyl, thiazolidinyl, imidazolinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl, benzimidazolonyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, morpholino, including, for example, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolanyl, benzodithianyl, 3-(1-alkyl)-benzimidazol-2-onyl, and 1,3-dihydro-imidazol-2-onyl.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkyl group, as defined herein, attached to the molecule through an oxygen (“alkoxy” e.g., —O-alkyl) or sulfur (“thioalkyl” e.g., —S-alkyl) atom.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy” (or “aminoalkyl”, “hydroxyalkyl” etc.,) mean alkyl, alkenyl, aliphatic, or alkoxy, as the case may be, substituted with one or more halogen atoms (or amino or hydroxy). The terms haloalkyl etc., include, mono- di- and tri-halo substituted groups. In particular, these terms include perfluorinated alkyl groups, such as —CF₃ and —CF₂CF₃.

The terms “halogen”, “halo”, and “hal” mean F, Cl, Br, or I.

The term “acyl group” means —C(O)R wherein R is an aliphatic groups as defined herein, or an aryl group as defined herein.

The term “aryl” used alone or as part of a larger moiety as in “heteroaryl”, “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to both carbocyclic and or heterocyclic aromatic ring systems. The term “aryl” may be used interchangeably with the term “aryl ring”.

Carbocyclic aromatic ring groups have only carbon ring atoms (typically six to fourteen) and include monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring systems in which one carbocyclic aromatic rings is fused to one or more aromatic rings in which the radical or point of attachment is on the carbocyclic aromatic ring. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scope of the term “carbocyclic aromatic ring”, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings (carbocyclic or heterocyclic), such as in an indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the carbocyclic aromatic ring.

The term “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroaryl group” and “heteroaromatic group”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromatic ring groups having five to fourteen members, including monocyclic heteroaromatic rings and polycyclic aromatic rings in which a monocyclic heteroaryl ring is fused to one or more other aromatic ring in which the radical or point of attachment is on the heteroaryl ring. Heteroaryl groups have one or more ring heteroatoms. Also included within the scope of the term “heteroaryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings (carbocyclic or heterocyclic), where the radical or point of attachment is on the heteroaryl ring. Bicyclic 6,5 heteroaromatic ring, as used herein, for example, is a six membered heteroaromatic ring fused to a second five membered ring, wherein the radical or point of attachment is on the six membered ring. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl including, for example, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, benzisoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

The terms “aralkyl”, “heteroaralkyl”, “cycloaliphaticalkyl”, and “heterocyclylakyl”, refer to alkyl groups as defined herein substituted with aryl, heteroaryl, cycloaliphatic, or heterocyclic groups respectively.

The term “protecting group” and “protective group” as used herein, are interchangeable and refer to an agent used to temporarily block one or more desired functional groups in a compound with multiple reactive sites. In certain embodiments, a protecting group has one or more, or preferably all, of the following characteristics: a) is added selectively to a functional group in good yield to give a protected substrate that is b) stable to reactions occurring at one or more of the other reactive sites; and c) is selectively removable in good yield by reagents that do not attack the regenerated, deprotected functional group. As would be understood by one skilled in the art, in some cases, the reagents do not attack other reactive groups in the compound. In other cases, the reagents may also react with other reactive groups in the compound. Examples of protecting groups are detailed in Greene, T. W., Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999 (and other editions of the book), the entire contents of which are hereby incorporated by reference. The term “nitrogen protecting group”, as used herein, refers to an agent used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the characteristics exemplified for a protecting group above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T. W., Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.

In some embodiments, where indicated a methylene unit of an aliphatic group or alkyl group is optionally replaced with another atom or group. Examples of such atoms or groups include, but are not limited to, —N(R′)—, —O—, —C(O)—, —C(═N—CN)—, —C(═NR′)—, —C(═NOR′)—, —S—, —S(O)—, and —S(O)₂—. These atoms or groups can be combined to form larger groups. Examples of such larger groups include, but are not limited to, —OC(O)—, —C(O)CO—, —CO₂—, —C(O)NR′—, —C(═N—CN), —N(R′)C(O)—, —N(R′)C(O)O—, —S(O)₂N(R′)—, —N(R′)SO₂—, —N(R′)C(O)N(R′)—, —OC(O)N(R′)—, and —N(R′)SO₂N(R′)—, wherein R′ is defined herein.

Only those replacement and combinations of groups that result in a stable structure are contemplated. Optional replacements can occur both within the chain and/or at either end of the chain; i.e. both at the point of attachment and/or also at the terminal end. Two optional replacements can also be adjacent to each other within a chain so long as it results in a chemically stable compound. The optional replacements can also completely replace all of the carbon atoms in a chain. For example, a C₃ aliphatic can be optionally replaced by —N(R′)—, —C(O)—, and —N(R′)— to form —N(R′)C(O)N(R′)— (a urea).

Unless otherwise indicated, if the replacement occurs at the terminal end, the replacement atom is bound to an H on the terminal end. For example, if a methylene unit in —CH₂CH₂CH₃ were optionally replaced with —O—, the resulting compound could be —OCH₂CH₃, —CH₂OCH₃, or —CH₂CH₂OH.

Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, geometric, conformational, and rotational) forms of the structure. For example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this invention. As would be understood to one skilled in the art, a substituent can freely rotate around any rotatable bonds. For example, a substituent drawn as

also represents

Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, geometric, conformational, and rotational mixtures of the present compounds are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

Additionally, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

As described herein, where indicated compounds and groups of the invention may optionally be substituted with one or more substituents, such as are illustrated generally herein, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Therefore, where it is not indicated that a compound or group is substituted, it is understood that the group is not substituted. That is, if the terms “optionally substituted” or “substituted” is not present in an instance of the definition of a compound or group it is understood that the compound or group is not substituted in that instance. For example, Ri is alkyl, Rii is optionally substituted alkyl, and Riii is alkyl optionally substituted with halo, means that Rii, and Riii are optionally substituted and Ri is not substituted in this instance.

Only those choices and combinations of substituents that result in a stable structure are contemplated. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.

The term “ring atom” is an atom such as C, N, O or S that is in the ring of an aromatic group, cycloalkyl group or non-aromatic heterocyclic ring.

A “substitutable ring atom” in an aromatic group is a ring carbon or nitrogen atom bonded to a hydrogen atom. The hydrogen can be optionally replaced with a suitable substituent group. Thus, the term “substitutable ring atom” does not include ring nitrogen or carbon atoms which are shared when two rings are fused. In addition, “substitutable ring atom” does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to a moiety other than hydrogen, or when the structure depicts they are already bound by a hydrogen.

An optionally substituted aryl group as defined herein contains one or more substitutable ring atoms, which may be optionally bonded to one or more suitable substituent. Examples of suitable substituents on a substitutable ring carbon atom of an aryl group includes Rk. Rk is —Ra, —Br, —Cl, —I, —F, —ORa, —SRa, —O—CORa, —CORa, —CSRa, —CN, —NO₂, —NCS, —SO₃H, —N(RaRb), —COORa, —NRcNRcCORa, —NRcNRcCO₂Ra, —CHO, —CON(RaRb), —OC(O)N(RaRb), —CSN(RaRb), —NRcCORa, —NRcCOORa, —NRcCSRa, —NRcCON(RaRb), —NRcNRcC(O)N(RaRb), —NRcCSN(RaRb), —C(═NRc)—N(RaRb), —C(═S)N(RaRb), —NRd—C(═NRc)—N(RaRb), —NRcNRaRb, —S(O)_(p)NRaRb, —NRcSO₂N(RaRb), —NRcS(O)_(p)Ra, —S(O)_(p)Ra, —OS(O)_(p)NRaRb or —OS(O)_(p)Ra; wherein p is 1 or 2.

Ra-Rd are each independently —H, an aliphatic group, aromatic group, non-aromatic carbocyclic or heterocyclic group or —N(RaRb), taken together, form a non-aromatic heterocyclic group. The aliphatic, aromatic and non-aromatic heterocyclic group represented by Ra-Rd and the non-aromatic heterocyclic group represented by —N(RaRb) are each optionally and independently substituted with one or more groups represented by Rl. Preferably Ra-Rd are unsubstituted.

Rl is halogen, R^(m), —SR^(m), —NO₂, —CN, —N(R^(m))₂, —COOR^(m), —NHCO₂R^(m), —NHC(O)R^(m), —NHNHC(O)R^(m), —NHC(O)N(R^(m))₂, —NHNHC(O)N(R^(m))₂, —NHNHCO₂R^(m), —C(O)N(R^(m))₂, —OC(O)R^(m), —OC(O)N(R^(m))₂, —S(O)₂R^(m), —SO₂N(R^(m))₂, —S(O)R^(m), —NHSO₂N(R^(m))₂, —NHSO₂R^(m), —C(═S)N(Rm⁺)₂, or —C(═NH)—N(R^(m))₂.

R^(m) is —H, a C1-C4 alkyl group, a monocyclic aryl group, a non-aromatic carbocyclic or heterocyclic group each optionally substituted with unsubstituted alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, —CN, —NO₂, amine, alkylamine or dialkylamine. Preferably R^(m) is unsubstituted.

An optionally substituted aliphatic or a non-aromatic heterocyclic or carbocyclic group as defined herein contains one or more substitutable atoms which may optionally be bonded to one or more suitable substituents. Examples of suitable substituents for an aliphatic group or a ring carbon of a non-aromatic heterocyclic group is Rn. Rn include those substituents listed above for Rk and ═O, ═S, ═NNHRo, ═NN(Ro)₂, ═NNHC(O)Ro, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), ═NRo, spiro cycloalkyl group or fused cycloalkyl group. Each Ro is independently selected from hydrogen, an unsubstituted alkyl group or a substituted alkyl group. Examples of substituents on the alkyl group represented by Ro include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl. Preferably Ro is unsubstituted.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted as indicated herein. When a nitrogen atom in the aromatic ring of a heteroaryl group has a substituent the nitrogen may be a quaternary nitrogen.

In certain embodiments non-aromatic nitrogen-containing heterocyclic group or heteroaryl groups are optionally substituted at the nitrogen ring atom. Suitable substituents on the nitrogen of a non-aromatic heterocyclic group or heteroaryl group include —Rq, —N(Rq)₂, —C(O)Rq, CO₂Rq, —C(O)C(O)Rq, —SO₂Rq, SO₂ N(Rq)₂, —C(═S)N(Rq)₂, —C(═NH)—N(Rq)₂, and —NRqSO₂Rq; wherein Rq is hydrogen, an aliphatic group, a substituted aliphatic group, aryl, substituted aryl, heterocyclic or carbocyclic ring or a substituted heterocyclic or carbocyclic ring. Examples of substituents on the group represented by R^(̂) include alkyl, haloalkoxy, haloalkyl, alkoxyalkyl, sulfonyl, alkylsulfonyl, halogen, nitro, cyano, hydroxy, aryl, carbocyclic or heterocyclic ring, oxo, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, carboxy, alkoxycarbonyl, or alkylcarbonyl. Preferably R^(̂) is not substituted.

Non-aromatic nitrogen containing heterocyclic rings and heteroaryl that are substituted on a ring nitrogen and attached to the remainder of the molecule at a ring carbon atom are said to be N substituted. For example, an N alkyl piperidinyl group is attached to the remainder of the molecule at the two, three or four position of the piperidinyl ring and substituted at the ring nitrogen with an alkyl group. Non-aromatic nitrogen containing heterocyclic rings such as piperazinyl that are substituted on a ring nitrogen and attached to the remainder of the molecule at a second ring nitrogen atom are said to be N′ substituted-N-heterocycles. For example, an N′ acyl N-piperazinyl group is attached to the remainder of the molecule at one ring nitrogen atom and substituted at the second ring nitrogen atom with an acyl group.

As used herein an optionally substituted aralkyl can be substituted on both the alkyl and the aryl portion. In certain embodiments, optionally substituted aralkyl is optionally substituted on the aryl portion.

The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

The compounds of this invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable salt.

As used herein, the term “pharmaceutically acceptable salt” refers to salts of a compound which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue side effects, such as, toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds. Acid addition salts can be prepared by I) reacting the purified compound in its free-based form with a suitable organic or inorganic acid and 2) isolating the salt thus formed.

Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

Base addition salts can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base and 2) isolating the salt thus formed. Salts derived from appropriate bases include alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N⁺(C₁₋₄alkyl)₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. Other acids and bases, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid or base addition salts.

It should be understood that this invention includes mixtures/combinations of different pharmaceutically acceptable salts and also mixtures/combinations of compounds in free form and pharmaceutically acceptable salts.

In addition to the compounds of this invention, pharmaceutically acceptable solvates (e.g., hydrates) and clathrates of the compounds of this invention may also be employed in compositions to treat or prevent the herein identified disorders.

As used herein, the term “pharmaceutically acceptable solvate,” is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds the invention. The term solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).

As used herein, the term “hydrate” means a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

As used herein, the term “clathrate” means a compound of the present invention or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.

In addition to the compounds of this invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of this invention may also be employed in compositions to treat or prevent the herein identified disorders.

As used herein and unless otherwise indicated, the term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may become active upon such reaction under biological conditions, or they may have activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of the invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of compounds of the invention that comprise —NO, —NO2, —ONO, or —ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).

A “pharmaceutically acceptable derivative” is an adduct or derivative which, upon administration to a patient in need, is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof. Examples of pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters.

A “pharmaceutically acceptable derivative or prodrug” includes any pharmaceutically acceptable ester, salt of an ester or other derivative or salt thereof of a compound, of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favoured derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.

As used herein, the phrase “side effects” encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful or uncomfortable or risky. Side effects include, but are not limited to fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction.

In one embodiment the present invention is a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment the present invention is a pharmaceutical composition comprising an effective amount of compound of the present invention and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.

A pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds. The pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic or devoid of other undesired reactions or side-effects upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed.

The pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.

Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

The protein kinase inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to a subject as defined herein. These pharmaceutical compositions, which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase-mediated condition and a pharmaceutically acceptable carrier, are another embodiment of the present invention.

In one embodiment the present invention is a method of treating or preventing a protein kinase-mediated disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound composition or a pharmaceutically acceptable salt of the present invention as described herein. In another embodiment, the present invention is the use of an effective amount of a compound, composition or a pharmaceutically acceptable salt described herein for treating or preventing a disease or disorder, described herein, in a subject in need thereof. In another embodiment, the present invention is the use of an effective amount of a compound, composition or a pharmaceutically acceptable salt described herein for treating a disease or disorder, described herein, in a subject in need thereof. In yet another embodiment, the present invention is the use of an effective amount of a compound, composition or a pharmaceutically acceptable salt described herein for the manufacture of a medicament method for the treatment or prevention of a disease or disorder, described herein, in a subject in need thereof. In yet another embodiment, the present invention is the use of an effective amount of a compound, composition or a pharmaceutically acceptable salt described herein for the manufacture of a medicament method for the treatment of a disease or disorder, described herein, in a subject in need thereof. In one embodiment the protein kinase mediated disease is a protein kinase C (PKC) mediated disease. In another embodiment the protein kinase mediated disease is a protein kinase C theta (PKCtheta)-mediated disease.

As used herein, the terms “subject”, “patient” and “mammal” are used interchangeably. The terms “subject” and “patient” refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a mammal including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more preferably a human. In one embodiment, the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a human.

As used herein, an “effective amount” refers to an amount sufficient to elicit the desired biological response. In the present invention the desired biological response is to reduce or ameliorate the severity, duration, progression, or onset of a protein kinase-mediated condition, prevent the advancement of a protein kinase-mediated condition, cause the regression of a protein kinase-mediated condition, prevent the recurrence, development, onset or progression of a symptom associated with a protein kinase-mediated condition, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy. The precise amount of compound administered to a subject will depend on the mode of administration, the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of protein kinase-mediated condition, and the mode of administration. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When co-administered with other agents, e.g., when co-administered with an protein kinase-mediated condition agent, an “effective amount” of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the invention being used. In cases where no amount is expressly noted, an effective amount should be assumed.

As used herein, the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of a protein kinase-mediated condition, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a protein kinase-mediated condition resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound of the invention). In specific embodiments, the terms “treat”, “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a protein kinase-mediated condition. In other embodiments the terms “treat”, “treatment” and “treating” refer to the inhibition of the progression of a protein kinase-mediated condition, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the terms “treat”, “treatment” and “treating” refer to the reduction or stabilization of a protein kinase-mediated condition.

As used herein, the terms “prevent”, “prevention” and “preventing” refer to the reduction in the risk of acquiring or developing a given protein kinase-mediated condition, or the reduction or inhibition of the recurrence or a protein kinase-mediated condition. In one embodiment, a compound of the invention is administered as a preventative measure to a patient, preferably a human, having a genetic predisposition to any of the conditions, diseases or disorders described herein.

As used herein, the terms, “disease”, “disorder” and “condition” may be used interchangeably here to refer to a protein kinase-mediated condition.

In one aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where a protein kinase is implicated in the disease state. In another aspect, the present invention provides a method for treating or lessening the severity of a kinase disease, condition, or disorder where inhibition of enzymatic activity is implicated in the treatment of the disease. In another aspect, this invention provides a method for treating or lessening the severity of a disease, condition, or disorder with compounds that inhibit enzymatic activity by binding to the protein kinase. Another aspect provides a method for treating or lessening the severity of a kinase disease, condition, or disorder by inhibiting enzymatic activity of the kinase with a protein kinase inhibitor. In some embodiments, said protein kinase inhibitor is a PKCtheta inhibitor.

The term “protein kinase-mediated condition”, as used herein means any disease or other deleterious condition in which a protein kinase plays a role. Such conditions include, without limitation, autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically-mediated diseases, immuno-deficiency disorders, immunomodulatory or immunosuppressive disorder, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone related diseases, diabetes, allergies, asthma, and Alzheimer's disease. In one embodiment, the protein-kinase mediated condition is a PKC-mediated condition.

The term “PKC-mediated condition”, as used herein means any disease or other deleterious condition in which PKC plays a role. Such conditions include, without limitation, those listed above, and in particular, T-cell mediated diseases, including without limitation autoimmune diseases, chronic or acute inflammatory diseases, and proliferative and hyperproliferative diseases. In one embodiment, the PKC-mediated condition is a PKCtheta-mediated condition

The term “PKCtheta-mediated condition”, as used herein means any disease or other deleterious condition in which PKCtheta plays a role. Such conditions include, without limitation, those listed above, and in particular, autoimmune diseases, chronic or acute inflammatory diseases, and proliferative and hyperproliferative diseases.

As used herein, the term “inflammatory disease” or “inflammatory disorder” refers to pathological states resulting in inflammation, typically caused by leukocyte infiltration. Examples of such disorders include inflammatory skin diseases, including, without limitation, psoriasis and atopic dermatitis; systemic scleroderma and sclerosis; responses associated with inflammatory bowel disease (IBD) (such as Crohn's disease and ulcerative colitis); ischemic reperfusion disorders including surgical tissue reperfusion injury, myocardial ischemic conditions such as myocardial infarction, cardiac arrest, reperfusion after cardiac surgery and constriction after percutaneous transluminal coronary angioplasty, stroke, and abdominal aortic aneurysms; cerebral edema secondary to stroke; cranial trauma, hypovolemic shock; asphyxia; adult respiratory distress syndrome; acute-lung injury; Behcet's Disease; dermatomyositis; polymyositis; multiple sclerosis (MS); dermatitis; meningitis; encephalitis; uveitis; osteoarthritis; lupus nephritis; autoimmune diseases such as rheumatoid arthritis (RA), Sjorgen's syndrome, vasculitis; diseases involving leukocyte diapedesis; central nervous system (CNS) inflammatory disorder, multiple organ injury syndrome secondary to septicaemia or trauma; alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex mediated diseases including glomerulonephritis; sepsis; sarcoidosis; immunopathologic responses to tissue or organ transplantation; inflammations of the lung, including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), and cystic fibrosis; etc.

Proliferative or hyperproliferative diseases are characterized by excessive or abnormal cell proliferation. Such diseases include, without limitation, cancer and myeloproliferative disorders.

The term “cancers” includes, but is not limited to, the following cancers: epidermoid Oral: Cardiac: Lung: Gastrointestinal: Genitourinary tract: Liver: Bone: Nervous system: Gynecological: Hematologic: Thyroid gland: and Adrenal glands. Hematologic cancers include: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma] hairy cell; lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and psoriasis. Thus, the term “cancerous cell” as provided herein, includes a cell afflicted by any one of the above-identified conditions.

The term “myeloproliferative disorders”, includes disorders such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, hypereosinophilic syndrome, juvenile myelomonocytic leukaemia, systemic mast cell disease, and hematopoietic disorders, in particular, acute-myelogenous leukemia (AML), chronic-myelogenous leukemia (CML), acute-promyelocytic leukemia (APL), and acute lymphocytic leukemia (ALL).

Examples of neurodegenerative diseases include, without limitation, Alzheimer's disease Huntington's disease, Parkinson's disease, AIDS-associated dementia, and bipolar disorder.

In one embodiment the PKCtheta mediated disease includes, without limitation, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other arthritic conditions, multiple sclerosis (MS), asthma, systemic lupus erythrematosis, adult respiratory distress syndrome, Behcet's disease, psoriasis, chronic pulmonary inflammatory disease, graft versus host reaction, Crohn's Disease, ulcerative colitis, inflammatory bowel disease (IBD), which includes celiac disease and irritable bowel syndrome; Alzheimer's disease, T-cell leukaemia, lymphoma, transplant rejection, cancer and pyresis, along with any disease or disorder that relates to inflammation and related disorders.

In one embodiment the PKCtheta mediated disease includes, diseases such as, but not limited to, arthritis, rheumatoid arthritis, osteoarthritis, joint inflammation, lupus, multiple sclerosis, asthma, psoriasis, cancer, T-cell lymphomas, leukaemia, diabetes type I or II, and inflammatory bowel diseases, transplant rejection, Crohn's disease and colitis.

Examples of autoimmune diseases include, without limitation, multiple sclerosis, rheumatoid arthritis and irritable bowel disease.

The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (iv particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include, but are not limited to, lactose and corn starch. Lubricating agents, such as, magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic; pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The dosage regimen utilizing the compounds of Structural Formula I, and IA can be selected in accordance with a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the renal and hepatic function of the subject; and the particular compound or salt thereof employed, the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The skilled artisan can readily determine and prescribe the effective amount of the compound of Structural Formula I, and IA required to treat, for example, to prevent, inhibit (fully or partially) or arrest the progress of the disease.

Dosages of the compounds of Structural Formula I, and IA can range from between about 0.01 to about 100 mg/kg body weight/day, about 0.01 to about 50 mg/kg body weight/day, about 0.1 to about 50 mg/kg body weight/day, or about 1 to about 25 mg/kg body weight/day. It is understood that the total amount per day can be administered in a single dose or can be administered in multiple dosings such as twice, three or four times per day.

The compounds for use in the method of the invention can be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.

An effective amount can be achieved in the method or pharmaceutical composition of the invention employing a compound of Structural Formula I, and IA or a pharmaceutically acceptable salt or solvate (e.g., hydrate) thereof alone or in combination with an additional suitable therapeutic agent, for example, a cancer-therapeutic agent. When combination therapy is employed, an effective amount can be achieved using a first amount of a compound of Structural Formula I, and IA or a pharmaceutically acceptable salt or solvate (e.g., hydrate) thereof and a second amount of an additional suitable therapeutic agent.

In one embodiment, the compound of Structural Formula I, and IA and the additional therapeutic agent, are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone). In another embodiment, the compound of Structural Formula I, and IA and the additional therapeutic agent, are each administered in an amount which alone does not provide a therapeutic effect (a sub-therapeutic dose). In yet another embodiment, the compound of Structural Formula I, and IA can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose. In still another embodiment, the compound of Structural Formula I, and IA can be administered in a sub-therapeutic dose, while the additional therapeutic agent, for example, a suitable cancer-therapeutic agent is administered in an effective amount.

As used herein, the terms “in combination” or “coadministration” can be used interchangeably to refer to the use of more than one therapies (e.g., one or more prophylactic and/or therapeutic agents). The use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.

Coadministration encompasses administration of the first and second amounts of the compounds of the coadministration in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each. In addition, such coadministration also encompasses use of each compound in a sequential manner in either order.

When coadministration involves the separate administration of the first amount of a compound of Structural Formula I, and IA and a second amount of an additional therapeutic agent, the compounds are administered sufficiently close in time to have the desired therapeutic effect. For example, the period of time between each administration which can result in the desired therapeutic effect, can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile. For example, a compound of Structural Formula I, and IA and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other.

More, specifically, a first therapy (e.g., a prophylactic or therapeutic agent such as a compound of the invention) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anti-cancer agent) to a subject.

It is understood that the method of coadministration of a first amount of a compound of Structural Formula I, and IA and a second amount of an additional therapeutic agent can result in an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the additive effect that would result from separate administration of the first amount of the compound of Structural Formula I, and IA and the second amount of the additional therapeutic agent.

As used herein, the term “synergistic” refers to a combination of a compound of the invention and another therapy (e.g., a prophylactic or therapeutic agent), which is more effective than the additive effects of the therapies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention, management or treatment of a disorder. In addition, a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of a disorder. Finally, a synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

The presence of a synergistic effect can be determined using suitable methods for assessing drug interaction. Suitable methods include, for example, the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S, and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)). Each equation referred to above can be applied with experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

In some embodiments, said additional therapeutic agent is selected from a cancer-therapeutic agent, such as, an anti-cancer agent, an anti-proliferative agent, or a chemotherapeutic agent.

In some embodiments, said additional therapeutic agent is selected from camptothecin, the MEK inhibitor: U0126, a KSP (kinesin spindle protein) inhibitor, adriamycin, interferons, and platinum derivatives, such as Cisplatin.

In other embodiments, said additional therapeutic agent is selected from taxanes; inhibitors of bcr-abl (such as Gleevec, dasatinib, and nilotinib); inhibitors of EGFR (such as Tarceva and Iressa); DNA damaging agents (such as cisplatin, oxaliplatin, carboplatin, topoisomerase inhibitors, and anthracyclines); and antimetabolites (such as AraC and 5-FU).

In yet other embodiments, said additional therapeutic agent is selected from camptothecin, doxorubicin, idarubicin, Cisplatin, taxol, taxotere, vincristine, tarceva, the MEK inhibitor, U0126, a KSP inhibitor, vorinostat, Gleevec, dasatinib, and nilotinib.

In another embodiment, said additional therapeutic agent is selected from Her-2 inhibitors (such as Herceptin); HDAC inhibitors (such as vorinostat), VEGFR inhibitors (such as Avastin), c-KIT and FLT-3 inhibitors (such as sunitinib), BRAF inhibitors (such as Bayer's BAY 43-9006) MEK inhibitors (such as Pfizer's PD0325901); and spindle poisons (such as Epothilones and paclitaxel protein-bound particles (such as Abraxane®).

Other therapies or anticancer agents that may be used in combination with the inventive agents of the present invention include surgery, radiotherapy (in but a few examples, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), Gleevec™, adriamycin, dexamethasone, and cyclophosphamide.

A compound of the instant invention may also be useful for treating cancer in combination with any of the following therapeutic agents: abarelix (Plenaxis Depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexylen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®); busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (Dromostanolone®); dromostanolone propionate (Masterone Injection®); Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®); Epoetin alfa (Epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine (intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelin Implant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex Tabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®); Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); zoledronate (Zometa®) and vorinostat (Zolinza®).

For a comprehensive discussion of updated cancer therapies see, http://www.nci.nih.gov/, a list of the FDA approved oncology drugs at http://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are hereby incorporated by reference.

Other examples of agents the compounds of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as Aricept® and Excelon®; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.

As inhibitors of protein kinases, the compounds and compositions of this invention are also useful in biological samples. One aspect of the invention relates to inhibiting protein kinase activity in a biological sample, which method comprises contacting said biological sample with a compound of Formula I, and IA or a composition comprising said compound. The term “biological sample”, as used herein, means an in vitro or an ex vivo sample, including, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of protein kinase activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, and biological specimen storage.

Another aspect of this invention relates to the study of protein kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such protein kinases; and the comparative evaluation of new protein kinase inhibitors. Examples of such uses include, but are not limited to, biological assays such as enzyme assays and cell-based assays.

The activity of the compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the kinase activity or ATPase activity of the activated kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and may be measured either by radiolabelling the inhibitor prior to binding, isolating the inhibitor/kinase complex and determining the amount of radiolabel bound, or by running a competition experiment where new inhibitors are incubated with the kinase bound to known radioligands. Detailed conditions for assaying a compound utilized in this invention are set forth in the Examples below.

Another aspect of the invention provides a method for modulating enzyme activity by contacting a compound of Formula I, and IA with a protein kinase.

ABBREVIATIONS

The following abbreviations are used:

DMSO dimethyl sulfoxide TCA trichloroacetic acid ATP adenosine triphosphate BSA bovine serum albumin DTT dithiothreitol MOPS 4-morpholinepropanesulfonic acid NMR nuclear magnetic resonance HPLC high performance liquid chromatography LCMS liquid chromatography-mass spectrometry TLC thin layer chromatography Rt retention time

In some embodiments, the compounds of this invention are represented in Table 1.

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

In some embodiments the variables used herein, such as, y, A, R₁, R₂, R₃, R₄, R₅, R₆, R₇, and B are as defined in Table 1.

General Synthetic Methodology

The compounds of this invention may be prepared in light of the specification using steps generally known to those of ordinary skill in the art. Those compounds may be analyzed by known methods, including but not limited to LCMS (liquid chromatography mass spectrometry) HPLC and NMR (nuclear magnetic resonance). It should be understood that the specific conditions shown below are only examples, and are not meant to limit the scope of the conditions that can be used for making compounds of this invention. Instead, this invention also includes conditions that would be apparent to those skilled in that art in light of this specification for making the compounds of this invention. Unless otherwise indicated, all variables in the following schemes are as defined herein. General Schemes:

Scheme 1 above describes a general synthetic route for preparing compounds of Formula I, and IA of this invention where R₂, R₃, R₄, R₅ and R₆ are as described herein (the five membered ring with A, A′, is defined as ring A herein, it is understood that ring B substituted with (R₇)_(y) can replace the CR₂R₃R₄ group). Cyclisation of 1 in presence of hydrazine furnishes intermediate 2. Introduction of a suitable protecting group (e.g. tosyl, trityl, Sem) followed by boronation of iodo derivative 3 gives 4. Suzuki coupling of intermediate 4 with bromo derivative 5 leads to 6 which yield compounds 7 of this invention after deprotection using conditions well know in the art.

Scheme 2 above describes another general synthetic route for preparing compounds of Formula I, and IA of this invention where R₂, R₃, R₄, R₅ and R₆ are as described herein (the five membered ring with A, A′, is defined as ring A herein, it is understood that ring B substituted with (R₇)_(y) can replace the CR₂R₃R₄ group). Starting materials for 8 are either commercially available or can be prepared by reactions well known in the art (e.g. Knochel, Buchwald). Boronation of derivative 8, followed by Suzuki-Miyaura cross-coupling reaction with intermediate 10 leads to compounds 11 of this invention.

Scheme 3 above shows a general synthetic route for preparing compounds of Formula I, and IA of this invention where R₂, R₃, R₄, R₅ and R₆ are as described herein (the five membered ring with A, A′, is defined as ring A herein), and R₂ is CH₂NH₂. Compounds 13 of this invention can be prepared by reduction of the cyano functionality using conditions well known in the art.

Scheme 4 above shows another general synthetic route for preparing compounds of Formula I, and IA of this invention where R₂, R₃, R₄, R₅ and R₆ are as described herein (the five membered ring with A, A′, is defined as ring A herein, it is understood that ring B substituted with (R₇)_(y) can replace the CR₂R₃R₄ group). Suzuki coupling of intermediate 15 with bromo derivatives 14 lead to compounds 16. Compounds 17 of this invention were finally obtained after deprotection of intermediates 16.

Scheme 5 above shows another general synthetic route for preparing compounds of Formula I, and IA of this invention where A, A′, R₂, R₃, R₄, R₅ and R₆ are as described herein (the five membered ring with A, is defined as ring A herein, it is understood that ring B substituted with (R₇)_(y) can replace the CR₂R₃R₄ group). Intermediate 18 was converted in the corresponding carboxilate derivative by quenching the Grignard intermediate with CO2. The carboxilate then is the transform in the primary amide 19. The compounds 19 were treated with Lawsson's reagent to produce the thioamide 20. Compounds of formula 20 were converted in the corresponding thiazoles by refluxing with conveniently substituted alpha bromo ketones. Compounds 22 of this invention were finally obtained after deprotection.

EXAMPLES HPLC Methods

Mass spec. samples were analyzed on a MicroMass Quattro Micro mass spectrometer operated in single MS mode with electrospray ionization. Samples were introduced into the mass spectrometer using chromatography. Mobile phase for all mass spec. analyses consisted of 10 mM pH 7 ammonium acetate and a 1:1 acetonitrile-methanol mixture. Column gradient conditions were 5%-100% acetonitrile-methanol over 3.5 mins gradient time and 4.8 mins run time on an ACE5C8 3.0×75 mm column. Flow rate was 1.2 ml/min.

As used herein, the term “Rt(min)” refers to the LCMS retention time, in minutes, associated with the compound. Unless otherwise indicated, the LCMS method utilized to obtain the reported retention time is as detailed above.

1H-NMR spectra were recorded at 400 MHz using a Bruker DPX 400 instrument.

The following compounds of Formula I, and IA were prepared and analyzed as follows.

Example 1 2-(2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl)ethanenitrile (Compound 1)

Method A Step 1: 4-iodo-1-trityl-1H-pyrazolo[3,4-b]pyridine

4-iodo-1H-pyrazolo[3,4-b]pyridine (15 g, 61.22 mmol) was dissolved in DMF (300 mL) and the solution was cooled down in an ice bath to 5° C. Sodium hydride (60%, 2.938 g, 73.46 mmol) was added portionwise and left to stir at this temperature for 2 hours. After this time a solution of trityl chloride (18.77 g, 67.34 mmol) in DMF (150 mL) was added dropwise over 30 minutes. After an additonal 2 hours of stirring, the solvent was removed by evaporation, and the residue was partitioned between ethyl acetate and saturated bicarbonate (2×100 ml). The organic layer was further washed with brine (100 ml), dried (MgSO₄) and concentrated in vacuo to give a brown oil. This residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (13.71 g, 46% Yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 7.16-7.31 (15H, m), 7.59 (1H, d), 7.89 (1H, d), 8.10 (1H, s); MS (ES⁺) 488.

Step 2: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine

A mixture of 4-iodo-1-trityl-1H-pyrazolo[3,4-b]pyridine (9.61 g, 19.72 mmol), potassium acetate (5.806 g, 59.16 mmol) and bis(pinacol)diboron (6.008 g, 23.66 mmol) was dissolved in dioxane (100 mL). Nitrogen was bubbled through the reaction mixture for 20 minutes then 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (805.2 mg, 0.99 mmol) was added in one portion and the reaction mixture was sealed and heated to 120° C. behind a blast shield for 24 hours. The reaction mixture was cooled down to room temperature, filtered through a path of celite and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified on silica gel by flash column chromatography to afford the title compound as a beige solid (7.08 g, 74% Yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 1.35 (12H, s), 7.19-7.32 (16H, m), 8.25-8.29 (2H, m); MS (ES) 488.

Step 3: (2-bromothiazol-4-yl)methanol

A solution of ethyl 2-bromothiazole-4-carboxylate (7.821 g, 33.13 mmol) in THF (100 mL) was cooled in an ice-bath and treated portionwise with lithium borohydride (1.083 g, 49.70 mmol). After 1 hour MeOH (1.614 g, 2.040 mL, 50.36 mmol) was added over a period of half an hour. The reaction was allowed to stir for 3 hours and then the solvent was concentrated in vacuo and the resultant residue was dissolved in EtOAc, washed with HCl (2×), saturated sodium bicarbonate, followed by brine, dried (Na₂SO₄), concentrated and purified by column chromatography (EtOAc/Petroleum ether 1:1) to give the required product as a colorless oil (4.30 g, 67% Yield). ¹H NMR (CDCl₃, 400 MHz) δ 2.51 (1H, m), 4.75 (2H, m), 7.19 (1H, s); MS (ES) 195.96

Step 4: 2-bromo-4-(iodomethyl)thiazole

A cooled solution of 2-bromothiazol-4-yl)methanol (1.488 g, 7.668 mmol), triphenylphosphine (3.016 g, 2.664 mL, 11.50 mmol) and 4H-imidazole (1.044 g, 15.34 mmol) in THF (20 mL) under nitrogen was treated with molecular iodine (2.919 g, 592.1 μL, 11.50 mmol) in one portion and the reaction maintained at this temperature. After 1 hour the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 1% sodium metabisulfite solution followed by brine and dried over MgSO₄. The mixture was concentrated in vacuo and purified using column chromatography (3:1 Petroleum ether/EtOAc) to give the pure product as a white solid (2.12 g, 91% Yield). NMR (CDCl₃, 400 MHz) δ 4.49 (2H, s), 7.22 (1H, s); MS (ES⁺) 305.74

Step 5: 2-(2-bromothiazol-4-yl)ethanenitrile

A solution of 2-bromo-4-(iodomethyl)thiazole (2.11 g, 6.942 mmol) in DMSO (15 mL) under nitrogen was treated with sodium cyanide (345.0 mg, 7.039 mmol) and allowed to stir for 40 minutes. The reaction was diluted with diethyl ether/water and the layers separated, the aqueous was extracted further with ether (2×) and the combined organics washed with brine, dried (Na₂SO₄), filtered and concentrated. The resultant residue was purified by column chromatography (3:1 Petroleum ether/EtOAc) to afford the product as a white solid (1.20 g, 86% Yield). ¹H NMR (CDCl₃, 400 MHz) δ 3.91 (2H, s), 7.31 (1H, s); MS (ES⁺) 204.95

Step 6: 2-(2-(1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl)ethanenitrile

A mixture of 2-(2-bromothiazol-4-yl)acetonitrile (575 mg, 2.832 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[3,4-b]pyridine (1.840 g, 3.398 mmol), Na₂CO₃ (4.248 mL of 2 M, 8.496 mmol) and tetrakis(triphenylphosphine) Palladium(0) (130.9 mg, 0.1133 mmol) was heated in the microwave at 150° C. for 20 minutes. The reaction mixture was treated with water/EtOAc and extracted twice. The organics were dried (MgSO₄), filtered, concentrated and purified (1:1 Petroleum ether/EtOAc,). The mixture was recolumned (Petroleum ether) to give the desired pure product (827 mg, 60% Yield). ¹H NMR (CDCl₃, 400 MHz) δ 4.04 (2H, s), 7.47 (2H, m), 8.34 (1H, m), 8.75 (1H, m); MS (ES⁺) 484.12

Step 7: 2-(2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl)ethanenitrile

A solution of 2-[2-(1-tritylpyrazolo[5,4-b]pyridin-4-yl)thiazol-4-yl]acetonitrile (83 mg, 0.1716 mmol) in DCM (3 ml) was treated with triethylsilane (0.5 ml) followed by TFA (0.5 mL). After 15 minutes the mixture was concentrated in vacuo and purified by column chromatography (70:9:1 DCM/MeOH/NH₄OH) to give the product as a light tan solid (6.5 mg, 16% Yield). ¹H NMR (DMSO, 400 MHz) δ 4.37 (2H, s), 7.72 (1H, d), 7.94 (1H, s), 8.63 (1H, s), 8.66 (1H, d), 13.98 (1H, br s); MS (ES⁺) 242.00

Example 2 2-(2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl)-2-methyl propanenitrile (Compound 2)

Compound 2 was prepared using Method A, Steps 1-6 followed by Method B, Steps 1-2.

Method B Step 1: 2-methyl-2-(2-(1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl)propanenitrile

A cooled solution of 2-[2-(1-tritylpyrazolo[5,4-b]pyridin-4-yl)thiazol-4-yl]acetonitrile (253 mg, 0.5232 mmol) in TI-IF (2 mL) under nitrogen was treated with LHMDS (1.024 g, 1.151 mL of 1 M in THF, 1.151 mmol) dropwise. The reaction mixture was allowed to stir at ambient temperature for 1.5 hours and then treated with MeI (185.7 mg, 81.45 μL, 1.308 mmol). The reaction mixture was allowed to stir overnight and then quenched with MeOH and concentrated. The residue was treated with EtOAc/brine and extracted twice. The combined organics were dried (MgSO₄), filtered and concentrated and purified by column chromatography (2:1 Petroleum ether/EtOAc) to give the product as a white foam: (239 mg, 89% Yield). MS (ES⁺) 512.20

Step 2: 2-(2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl)-2-methyl propanenitrile

A solution of 2-methyl-2-[2-(1-tritylpyrazolo[5,4-b]pyridin-4-yl)thiazol-4-yl]propanenitrile (239 mg, 0.4671 mmol) in DCM (6 mL) was treated with triethylsilane (727.8 mg, 999.7 μL, 6.259 mmol) followed by dropwise addition of TFA (296.0 mg, 200.0 μL, 2.596 mmol). The mixture was allowed to stir for 1 hour and then concentrated in vacuo and purified by column chromatography (EtOAc) to give the desired product as a yellow solid (97.5 mg, 78% Yield). ¹H NMR (DMSO, 400 MHz) δ 1.84 (6H, s), 7.73 (1H, d), 8.04 (1H, s), 8.64 (1H, s), 8.67 (1H, d), 13.98 (1H, br s); MS (ES⁺) 270.03

The following compounds were prepared in general by a similar route to that described in Example 2.

Compound 5 Compound 6 Compound 7 Example 3 2-(2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl)-2-methylpropan-1-amine (Compound 3)

Compound 3 was prepared using Method A, Steps 1-6 followed by Method B, Steps 1-2 followed by Method C, Step 1.

Method C Step 1: 2-(2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl)-2-methylpropan-1-amine

Alumane; N,N-dimethylethanamine (1.842 mL of 0.5 M, 0.9208 mmol) was added dropwise to a solution of 2-methyl-2-[2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl]propanenitrile (62 mg, 0.2302 mmol) in THF (7.5 mL) with ice bath cooling over a period of 10 minutes. The mixture was allowed to warm to RT overnight: Reaction was incomplete and therefore it was cooled again in an ice bath and treated with further Alumane; N,N-dimethylethanamine (1.842 mL of 0.5 M, 0.9208 mmol) over 3 minutes. The reaction mixture was left to stir for 6 hours and then cooled (with the aid of an ice bath) and treated dropwise with water. The aqueous was treated with saturated NaCl and extracted with EtOAc (3×), dried (MgSO₄) filtered and evaporated to dryness. The resultant residue was purified by column chromatography (70:9:1 DCM/MeOH/NH₄OH) to give the title compound which was lyophilized to give an off-white solid (63 mg, 19% Yield). ¹H NMR (DMSO, 400 MHz) δ 1.35 (6H, s), 2.83 (2H, s), 7.64 (1H, s), 7.66 (1H, d), 8.62 (1H, s), 8.63 (1H, d); MS (ES⁺) 274.04

The following compounds were prepared in general by a similar route to that described in Example 3.

Compound 9

Compound 10

Compound 119

Example 4 2-(2-(3-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl)-2-methylpropanenitrile (Compound 8)

Compound 8 was prepared using Method A, Steps 1-6 followed by Method B, Steps 1-2 followed by Method D, Step 1.

Method D Step 1: 2-(2-(3-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl)-2-methylpropanenitrile

2-methyl-2-[2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl]butanenitrile (82 mg, 0.2894 mmol) was suspended in a solution of NaOH (46.32 mg, 1.158 mmol) in Water (5.000 mL). The mixture was sonicated to give smaller particle size and cooled in an ice-bath. Sodium hypochlorite (282.8 μL of 8% w/v, 0.3039 mmol) was added slowly dropwise over 2 minutes and the resultant mixture was stirred at ambient temperature for 3 hours. The reaction was diluted with saturated aqueous Na₂CO₃ and then extracted twice with EtOAc. The combined organics were dried (MgSO₄), filtered, concentrated and purified by column chromatography (1:1, Petroleum ether/EtOAc) to give the pure compound as a white solid (3.9 mg, 4% Yield). ¹H NMR (DMSO, 400 MHz) δ 0.93 (3H, t), 1.76 (3H, s), 1.99-2.21 (2H, m), 7.54 (1H, s), 8.00 (1H, s), 8.71 (1H, s), 14.29 (1H, br s); MS (ES⁺) 318.08

Example 5 2-methyl-2-(5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl)propan-1-amine (Compound 4)

Compound 4 was prepared using Method A, Step 1 followed by Method E, Steps 1-5.

Method E Step 1: 1-trityl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

A solution of Isopropylmagnesium chloride-lithium chloride complex (21.99 mL of 14% w/v, 21.20 mmol) in THF (2.5 mL) was cooled to below −20° C. This was treated with 4-iodo-1-trityl-pyrazolo[5,4-b]pyridine (9.84 g, 20.19 mmol) under nitrogen and allowed to stir for 30 minutes. The reaction was then treated with 3 pellets of CO₂ and allowed to warm up. After a further hour the mixture was diluted with EtOAc and acidified with saturated aqueous ammonium chloride. The layers were separated, dried (MgSO₄), filtered and concentrated in vacuo. The mixture was purified by column chromatography (1:1 Petroleum ether/EtOAc moving to 10% MeOH/EtOAc) to give the product as an off-white oil (7.0 g, 86% Yield). ¹H NMR (DMSO, 400 MHz) δ 7.17-7.26 (15H, m), 7.47-7.49 (1H, m), 8.18 (1H, d), 8.56-8.58 (1H, m).

Step 2: 1-trityl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

A suspension of 1-tritylpyrazolo[5,4-b]pyridine-4-carboxylic acid (3.996 g, 9.856 mmol) in DMF (70.01 mL) was treated sequentially with triethylamine (2.194 g, 3.022 mL, 21.68 mmol), ammonium chloride (2.636 g, 1.723 mL, 49.28 mmol) and TBTU (4.746 g, 14.78 mmol) at RT under nitrogen. The reaction was allowed to stir for 4 hours and then treated with DCM and saturated aqueous NH₄Cl. The aqueous was extracted twice with DCM and the organic layer washed with aqueous NH₄Cl, followed by 0.5M NaOH, dried (MgSO₄), filtered and concentrated. The residue was purified by column chromatography (70:9:1 DCM/MeOH/NH₄OH) to give the product as white solid (3.08 g, 77% Yield). ¹H NMR (DMSO, 400 MHz) δ 7.18-7.29 (15H, m), 7.44 (1H, m), 7.83 (1H, br s), 8.27 (1H, br s), 8.37 (1H, m), 8.46 (1H, m); MS (ES⁺) 405.12

Step 3: 1-trityl-1H-pyrazolo[3,4-b]pyridine-4-carbothioamide

A solution of 1-tritylpyrazolo[5,4-b]pyridine-4-carboxamide (2.843 g, 7.029 mmol) in THF (50 mL) was treated with Lawesson's reagent (2.843 g, 7.029 mmol) at RT under nitrogen. The resulting yellow solution was allowed to heat at 80° C. for 4 hours and then treated with brine and extracted with EtOAc (2×). The organics were dried (Na₂SO₄), filtered, concentrated and purified by column chromatography (2% MeOH/DCM) to give the product as a yellow foam (quantitative yield). ¹H NMR (DMSO, 400 MHz) δ 7.18-7.30 (16H, m), 8.28 (1H, m), 8.40 (1H, s), 10.34 (1H, br s); MS (ES⁺) 421.16

Step 4: N-(2-methyl-2-(5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl)propyl)benzamide

A solution of 1-tritylpyrazolo[5,4-b]pyridine-4-carbothioamide (274 mg, 0.6516 mmol) N-(4-bromo-2,2-dimethyl-3-oxo-pentyl)benzamide (203.4 mg, 0.6516 mmol) in EtOH. (6.999 mL) was heated at 90° C. for 16 hours. The mixture was treated with aqueous saturated Na₂CO₃ and EtOAc and the two layers separated. The organic layer was dried (MgSO₄), filtered and concentrated and purified by column chromatography (70:9:1 DCM/MeOH/NH₄OH) to give the required product (103 mg, 40% Yield). ¹H NMR (CDCl₃, 400 MHz) δ 0.38-0.73 (6H, s), 1.79 (3H, s), 3.07 (2H, s), 6.36 (3H, m), 6.78 (3H, m), 7.80 (2H, m), 10.81 (1H, br s); MS (ES⁺) 392.03

Step 5: 2-methyl-2-(5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl)propan-1-amine

N-[2-methyl-2-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl]propyl]benzamide (55 mg, 0.1405 mmol) was dissolved in EtOH (1 mL) and treated with 5M NaOH (2.5 mL). The reaction was heated at 170° C. in the microwave for 500 minutes. The mixture was extracted with EtOAc followed by DCM and the combined organics were dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by column chromatography (70:9:1, DCM/MeOH/NH₄OH) to give the required product as a pale lemon solid (18.9 mg, 47% Yield). ¹H NMR (DMSO, 400 MHz) δ 1.40 (6H, s), 2.61 (3H, s), 2.88 (2H, s), 7.51 (1H, s), 8.56 (2H, m); MS (ES⁺) 288.00

Example 6 (4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methanamine (Compound 12)

Compound 12 was prepared using Method A, Step 1 followed by Method E, Steps 1-3 followed by Method F, Steps 1-2.

Method F Step 1: 4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-4-carbonitrile

A solution of 1-tritylpyrazolo[5,4-b]pyridine-4-carbothioamide (220 mg, 0.5232 mmol) and 3-bromo-1-methyl-2-oxo-cyclohexane-1-carbonitrile (125.0 mg, 0.5785 mmol) in EtOH (10 mL)/THF (1.5 mL) was heated at 90° C. overnight under nitrogen. The reaction mixture was concentrated in vacuo and purified by column chromatography (70:9:1 DCM/MeOH/NH₄OH) to give a white solid after precipitation (67 mg, 39% Yield). MS (ES⁺) 296.08

Step 2: (4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methanamine

A solution of 4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-6,7-dihydro-5H-1,3-benzothiazole-4-carbonitrile (67 mg, 0.2268 mmol) in THF (7 mL) was allowed to cool in an ice bath and treated with LiAlH₄ in THF (453.6 μL of 2 M, 0.9072 mmol) dropwise. The mixture was allowed to warm to RT, stirred for 3 hours and then quenched with water whilst cooling. The aqueous layer was extracted with EtOAc (2×) and the combined organics dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH₃CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (2.7 mg, 4% Yield). ¹H NMR (DMSO, 400 MHz) δ 1.29 (3H, s), 1.50-1.55 (1H, m), 1.85-1.98 (3H, m), 2.77-2.93 (4H, m), 7.58 (1H, d), 8.58 (1H, s), 8.60 (1H, d); MS (ES⁺) 300.05

Example 7 2-(4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-pyrazol-1-yl)butanenitrile (Compound 15)

Compound 15 was prepared using Method A, Step 1 followed by Method G, Steps 1-3.

Method G Step 1: 4-(1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine

A mixture of 4-iodo-1-trityl-pyrazolo[5,4-b]pyridine (1.404 g, 2.880 mmol), 444,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-pyrazole (950 mg, 4.896 mmol) and tetrakis(triphenylphosphine)palladium(0) (166.4 mg, 0.1440 mmol) in DME (20 mL) was treated with Na₂CO₃ (5.559 g, 5.040 mL of 2 M, 10.08 mmol) and heated in the microwave for 60 minutes at 150° C. The reaction mixture was diluted with EtOAc and water and the layers separated. The organics were dried (MgSO₄), filtered and concentrated and purified by column chromatography (1:1 Petroleum ether/EtOAc moving to EtOAc to) give the pure compound as a white solid (597 mg, 49% Yield). ¹H NMR (DMSO, 400 MHz) δ 6.25 (1H, m), 7.20-7.25 (15H, m), 7.33 (1H, m), 7.65 (2H, m), 8.19 (1H, m), 8.71 (1H, s), 8.60 (1H, br s); MS (ES⁺) 428.18

Step 2: 2-(4-(1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-pyrazol-1-yl)ethanenitrile

A mixture of 4-(1H-pyrazol-4-yl)-1-trityl-pyrazolo[5,4-b]pyridine (3.824 g, 8.945 mmol) and potassium carbonate (9.890 g, 71.56 mmol) in dry THF (100.0 mL) was treated with 2-bromoacetonitrile (8.583 g, 4.984 mL, 71.56 mmol) and heated at 90° C. for 5 hours. The reaction was allowed to cool and treated with brine/ EtOAc and the 2 layers separated. The combined organics were dried (MgSO₄), filtered, concentrated and purified by column chromatography (1:1 Petroleum ether/EtOAc) to give a white solid on concentration. The material was taken forward to the next step. ¹H NMR (CDCl₃, 400 MHz) δ 5.21 (2H, s), 7.06 (1H, s), 7.27-7.28 (15H, m), 8.04 (2H, m), 8.25 (2H, m); MS (ES⁺) 467.19

Step 3: 2-(4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-pyrazol-1-yl)butanenitrile

A solution of diisopropylamine (229.8 mg, 318.3 μL, 2.271 mmol) in THF (10 mL) at 0° C. was treated with butyllithium (698.8 μL of 2.5 M, 1.747 mmol) and then allowed to cool to −78° C. This was then added dropwise to a solution of 2-[4-(1-tritylpyrazolo[5,4-b]pyridin-4-yl)pyrazol-1-yl]acetonitrile (815 mg, 1.747 mmol) over a period of 20 minutes. After a further 30 minutes the reaction was treated with iodoethane (544.9 mg, 279.4 μL, 3.494 mmol) at −78° C. and the ice bath removed. The reaction was allowed to stir for 1.5 hours and then treated with brine/EtOAc and the two layers separated. The organics were dried (MgSO₄), filtered and concentrated. The resultant residue was taken up in DCM (12 mL) and treated with triethylsilane (4 mL) and TFA (0.5 mL) and allowed to stir at RT for 2 hours. The reaction was concentrated in vacuo and purified by column chromatography (10% MeOH/DCM) to give the product as a pure white solid (252 mg, 57% Yield). ¹H NMR (DMSO, 400 MHz) δ 0.95 (3H, t), 2.23-2.28 (2H, m), 5.79 (1H, t), 7.46 (1H, d), 8.46 (1H, s), 8.48 (1H, d), 8.52 (1H, d), 8.83 (1H, s), 13.73 (1H, br s); MS (ES⁺) 253.09

Example 8 2-(4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-pyrazol-1-yl)butan-1-amine (Compound 17)

Compound 17 was prepared using Method A, Step 1 followed by Method G, Steps 1-3 followed by Method H, Step 1.

Method H Step 1: 2-(4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-pyrazol-1-yl)butan-1-amine

To a stirred solution of 2-[4-(1H-pyrazolo[3,4-b]pyridin-4-yl)pyrazol-1-yl]butanenitrile (252 mg, 0.9989 mmol) in THF (10 mL) cooled in an ice bath was added LiAlH₄ (1.998 mL of 2 M, 3.996 mmol) dropwise over 10 minutes. The reaction was allowed to stir for 1.5 hours at RT and then quenched dropwise with MeOH and concentrated in vacuo. The residue was filtered through a Celite pad with the aid of MeOH and then purified by reverse phase preparative HPLC [Waters

Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH₃CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (26.2 mg, 10% Yield). ¹H NMR (DMSO, 400 MHz) δ 0.72 (3H, t), 1.41 (2H, br s), 1.80-1.86 (2H, m), 2.88-2.94 (2H, m), 4.09-4.13 (1H, m), 7.41 (1H, d), 8.31 (1H, s), 8.45 (1H, d), 8.57 (1H, s), 8.65 (1H, s), 13.62 (1H, br s); MS (ES⁺) 257.03

The following compound was prepared in general by a similar route to that described in Example 8.

Compound 16

Example 9 2-(5-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiophen-3-yl)-2-methylbutan-1-amine (Compound 13)

Compound 13 was prepared using Method I, Steps 1-5.

Method I Step 1: 2-(thiophen-3-yl)butanenitrile

A cooled solution of 2-(3-thienyl)acetonitrile (3.144 g, 25.52 mmol) in THF (30 mL) under nitrogen was treated with LHMDS in THF (22.70 g, 25.51 mL of 1 M, 25.50 mmol) dropwise over a period of 20 minutes. The mixture was allowed to stir for 30 minutes and then treated with iodoethane (4.180 g, 2.144 mL, 26.80 mmol) dropwise. The reaction was stirred at RT for a further hour and then quenched by the addition of MeOH and concentrated in vacuo. The residue was diluted with water and extracted with EtOAc (2×). The combined organics were dried (MgSO₄), filtered, concentrated and purified by column chromatography (6:1 Petroleum ether/EtOAc) to give the product as an oil (708 mg, 18% Yield). ¹H NMR (CDCl₃, 400 MHz) δ 1.08 (3H, t), 1.93-2.00 (2H, q), 3.86 (1H, m), 7.03 (1H, m), 7.25 (1H, m), 7.37 (1H, m)

Step 2: 2-methyl-2-(thiophen-3-yl)butanenitrile

A cooled solution of 2-(thiophen-3-yl)butanenitrile (708 mg, 4.682 mmol) in THF (15 mL) under nitrogen was treated with LHMDS in THF (4.375 g, 4.916 mL of 1 M, 4.916 mmol) dropwise. After 1 hour the reaction was treated with iodomethane (731.0 mg, 320.6 μL, 5.150 mmol) and then allowed to warm to RT. After 2.5 hours the reaction was quenched with MeOH and then concentrated in vacuo. The mixture was diluted with EtOAc/water and the two layers separated. The combined organics were dried (MgSO₄), filtered, concentrated and purified by column chromatography (5:1 Petroleum ether/EtOAc) to give the product as a colourless oil (693 mg, 90% Yield).

Step 3: 2-(5-bromothiophen-3-yl)-2-methylbutanenitrile

A solution of 2-methyl-2-(3-thienyl)butanenitrile (695 mg, 4.206 mmol) in acetic acid (5 mL) at RT was treated dropwise with molecular bromine (672.2 mg, 216.7 μL, 4.206 mmol) in acetic acid (1.5 mL) and allowed to stir for 3.5 hours. The mixture was treated with aqueous sodium thiosulfate and petroleum ether and the two layers separated. The organics were dried (MgSO4), filtered, concentrated and purified by column chromatography (10:1 Petroleum ether/EtOAc) to give the required product (911 mg, 47% Yield). ¹H NMR (CDCl3, 400 MHz) δ 1.06 (3H, m), 1.70 (3H, s), 1.94 (2H, m), 7.00 (1H, m), 7.20 (1H, m)

Step 4: 2-(5-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiophen-3-yl)-2-methylbutanenitrile

A mixture of 2-(5-bromo-3-thienyl)-2-methyl-butanenitrile (789 mg, 3.232 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[3,4-b]pyridine (1.750 g, 3232 mmol), Na2CO3 (4.848 mL of 2 M, 9.696 mmol) and tetrakis(triphenylphosphine) palladium(0) (112.0 mg, 0.09696 mmol) in DME (12 mL) was heated at 150° C. for 10 minutes in the microwave. The mixture was treated with water/EtOAc and the two layers separated. The organics were dried (MgSO₄), filtered, concentrated and the resultant residue was dissolved in DCM (8 mL) and treated with triethylsilane (5 mL) and TFA (1.5 mL) at RT. The reaction was allowed to stir for 2 hours, concentrated in vacuo and purified by column chromatography (1:1 to 2:1 Petroleum ether/EtOAc) to give the required product (236 mg, 26% Yield). ¹H NMR (CDCl3, 400 MHz) δ 1.06 (3H, m), 1.78 (3H, s), 2.05 (2H, m), 7.49 (1H, m), 7.53 (1H, m), 7.63 (1H, m), 8.42 (1H, m), 8.60 (1H, m); MS (ES⁺) 283.09

Step 5: 2-(5-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiophen-3-yl)-2-methylbutan-1-amine

A cooled solution of 2-methyl-2-[5-(1H-pyrazolo[3,4-b]pyridin-4-yl)-3-thienyl]butanenitrile (234 mg, 0.8287 mmol) in THF (10.00 mL) was treated with LiAlH4 in THF (1.658 mL of 2 M, 3.315 mmol) dropwise over a period of 3 minutes. The reaction was allowed to stir at RT overnight and then quenched with water whilst cooling. The mixture was extracted with EtOAc (2×) and the organics dried (MgSO₄), filtered, concentrated and purified by column chromatography (70:9:1 DCM/MeOH/NH₄OH) to give the product as a white solid (19.0 mg, 8% Yield). ¹H NMR (DMSO, 400 MHz) δ 0.71 (3H, t), 1.25 (3H, s), 1.50-1.64 (1H, m), 1.70-1.84 (1H, m), 2.67 (1H, d), 2.79 (1H, d), 7.46-7.48 (2H, m), 7.89 (1H, s), 8.48 (1H, s), 8.50 (1H, d); MS (ES⁺) 287.09

The following compound was prepared in general by a similar route to that described in Example 9.

Compound 14

Table 2 below depicts data for certain exemplary compounds made in general by a similar route to that outlined in the Examples above.

TABLE 2 M + 1 RT # (obs) (min) 1H-NMR 1 242.01 2.45 (DMSO, 400 MHz): 4.37 (2H, s), 7.72 (1H, d), 7.94 (1H, s), 8.63 (1H, s), 8.66 (1H, d), 13.98 (1H, br s). 2 270.04 2.86 (DMSO, 400 MHz) 1.84 (6H, s), 7.73 (1H, d), 8.04 (1H, s), 8.64 (1H, s), 8.67 (1H, d), 13.98 (1H, br s). 3 274.04 2.05 (400 MHz, DMSO) 1.35 (6H, s), 2.83 (2H, s), 7.64 (1H, s), 7.66 (1H, d), 8.62 (1H, s), 8.63 (1H, d). 4 288 2.62 (DMSO, 400 MHz) 1.40 (6H, s), 2.61 (3H, s), 2.89 (2H, s), 7.51 (1H, s), 8.56 (1H, app br s). 5 270.03 2.77 (DMSO, 400 MHz) 1.06 (3H, t), 2.08-2.12 (2H, m), 4.59 (1H, t), 7.72 (1H, d), 7.99 (1H, s), 8.63 (1H, s), 8.66 (1H, d), 14.00 (1H, br s). 6 284.05 2.94 (DMSO, 400 MHz) 0.97 (3H, t), 1.79 (3H, s), 2.03-2.51 (2H, m), 7.72 (1H, d), 8.01 (1H, s), 8.63 (1H, s), 8.66 (1H, d), 13.98 (1H, br s). 7 298.06 3.16 (DMSO, 400 MHz) 0.92 (6H, t), 2.10-2.21 (4H, m), 7.72 (1H, d), 7.99 (1H, s), 8.63 (1H, s), 8.66 (1H, d), 13.98 (1H, br s). 8 318.08 3.13 (DMSO, 400 MHz) 0.95 (3H, t), 1.77 (3H, s), 1.99-2.08 (1H, m), 2.16-2.21 (1H, m), 7.57 (1H, d), 8.00 (1H, s), 8.71 (1H, d), 14.29 (1H, s). 9 274.07 1.96 (DMSO, 400 MHz): 0.82 (3H, t), 1.70-1.86 (2H, m), 2.83-2.97 (3H, m), 7.65 (1H, s), 7.68 (1H, d), 8.60 (1H, s), 8.63 (1H, d). 10 (DMSO, 400 MHz) 0.73 (3H, t), 1.32 (3H, s), 1.64-1.70 (1H, m), 1.86-1.91 (1H, m), 2.78 (1H, d), 2.94 (1H, d), 7.62 (1H, s), 7.66 (1H, d), 8.61 (1H, s), 8.63 (1H, d). 11 (400 MHz, DMSO) 0.69 (3H, t), 1.29 (3H, s), 1.60-1.65 (1H, m), 1.81-1.88 (1H, m), 2.75 (1H, d), 2.93 (1H, d), 7.50 (1H, d), 7.60 (1H, s), 8.67 (1H, d). 12 300.05 2.18 (DMSO, 400 MHz) 1.29 (3H, s), 1.50-1.55 (1H, m), 1.85-1.98 (3H, m), 2.77-2.93 (4H, m), 7.58 (1H, d), 8.58 (1H, s), 8.60 (1H, d). 13 287.09 2.13 (DMSO, 400 MHz) 0.71 (3H, t), 1.25 (3H, s), 1.50-1.64 (1H, m), 1.70-1.84 (1H, m), 2.67 (1H, d), 2.79 (1H, d), 7.46-7.48 (2H, m), 7.89 (1H, s), 8.48 (1H, s), 8.50 (1H, d). 14 287.07 2.13 (400 MHz, DMSO) 0.64 (3H, t), 0.90 (3H, s), 1.24-1.31 (1H, m), 1.52-1.59 (1H, m), 2.44 (1H, d), 2.68 (1H, d), 7.14 (1H, d), 7.22 (1H, d), 7.64 (1H, d), 7.95 (1H, s), 8.52 (1H, d). 15 253.09 2.36 (DMSO, 400 MHz) 0.95 (3H, t), 2.23-2.28 (2H, m), 5.79 (1H, t), 7.46 (1H, d), 8.46 (1H, s), 8.48 (1H, d), 8.52 (1H, d), 8.83 (1H, s), 13.73 (1H, br s). 16 229.05 0.66 (DMSO, 400 MHz) 2.99 (2H, t), 4.18 (2H, t), 7.38 (1H, t), 8.28 (1H, s), 8.44 (1H, d), 8.53 (1H, s), 8.65 (1H, s), 13.69 (1H, br s). 17 257.07 1.63 (DMSO, 400 MHz) 0.72 (3H, t), 1.41 (2H, br s), 1.80-1.86 (2H, m), 2.88-2.94 (2H, m), 4.09-4.13 (1H, m), 7.41 (1H, d), 8.31 (1H, s), 8.45 (1H, d), 8.57 (1H, s), 8.65 (1H, s), 13.62 (1H, br s).

Example 10 PKC Theta

An assay buffer solution was prepared which consisted of 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 0.1 mM EDTA and 0.01% Brij. An enzyme buffer containing reagents to final assay concentrations of 0.00001% Triton X-100, 200 μg/mL Phosphatidylserine, 20 μg/mL Diacylglycerol, 360 μM NADH, 3 mM phosphoenolpyruvate, 70 μg/mL pyruvate kinase, 24 μg/mL lactate dehydrogenase, 2 mM DTT, 100 μM substrate peptide (ERMRPRKRQGSVRRRV SEQ ID NO. 1) and 18 nM PKC theta kinase was prepared in assay buffer. To 60 μL of this enzyme buffer, in a 384 well plate, was added 2 μL of VRT stock solution in DMSO. The mixture was allowed to equilibrate for 10 mins at 30° C. The enzyme reaction was initiated by the addition of 5 μL stock ATP solution prepared in assay buffer to a final assay concentration of 240 μM. Initial rate data was determined from the rate of change of absorbance at 340 nM (corresponding to stoichiometric consumption of NADH) using a Molecular Devices Spectramax plate reader (Sunnyvale, Calif.) over 15 mins at 30° C. For each Ki determination 12 data points covering the VRT concentration range of 0-20 μM were obtained in duplicate (DMSO stocks were prepared from an initial 10 mM VRT stock with subsequent 1:2 serial dilutions). Ki values were calculated from initial rate data by non-linear regression using the Prism software package (Prism 4.0a, Graphpad Software, San Diego, Calif.). Ki values are represented as A<0.05 μM, B<0.5 μM, C<2.8 μM, C**>1.25 μM, D*>2.0 μM, D>2.8 μM.

A compounds are: 2, 3, 5, 6, 7, 8, 9, 10, 11, and 13. B compounds are: 1, 4, 12, 14, 15, and 16. C compounds are: 17.

PKC Delta

An assay buffer solution was prepared which consisted of 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 0.1 mM EDTA and 0.01% Brij. An enzyme buffer containing reagents to final assay concentrations of 0.002% Triton X-100, 200 μg/mL Phosphatidylserine, 20 μg/mL Diacylglycerol, 360 μM NADH, 3 mM phosphoenolpyruvate, 70 μg/mL pyruvate kinase, 24 μg/mL lactate dehydrogenase, 2 mM DTT, 150 μM substrate peptide (ERMRPRKRQGSVRRRV SEQ ID NO. 2) and 46 nM PKC delta kinase was prepared in assay buffer. To 16 μL of this enzyme buffer, in a 384 well plate, was added 1 μL of VRT stock solution in DMSO. The mixture was allowed to equilibrate for 10 mins at 30° C. The enzyme reaction was initiated by the addition of 16 μL stock ATP solution prepared in assay buffer to a final assay concentration of 150 μM. Initial rate data was determined from the rate of change of absorbance at 340 nM (corresponding to stoichiometric consumption of NADH) using a Molecular Devices Spectramax plate reader (Sunnyvale, Calif.) over 15 mins at 30° C. For each Ki determination 12 data points covering the VRT concentration range of 0-20 μM were obtained in duplicate (DMSO stocks were prepared from an initial 10 mM VRT stock with subsequent 1:2 serial dilutions). Ki values were calculated from initial rate data by non-linear regression using the Prism software package (Prism 4.0a, Graphpad Software, San Diego, Calif.).

A compounds are: 11. B compounds are: 2, 3, 4, 5, 6, 7, 8, 9, 10, and 13. C compounds are: 1, 12, 15, 16, and 17. D* compounds are 14.

PKC Alpha

An assay buffer solution was prepared which consisted of 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 0.1 mM EDTA, 100 μM CaCl₂ and 0.01% Brij. An enzyme buffer containing reagents to final assay concentrations of 0.002% Triton X-100, 100 μg/mL Phosphatidylserine, 20 μg/mL Diacylglycerol, 360 μM NADH, 3 mM phosphoenolpyruvate, 70 pyruvate kinase, 24 μg/mL lactate dehydrogenase, 2 mM DTT, 150 μM substrate peptide (RRRRRKGSFKRKA SEQ ID NO. 3) and 4.5 nM PKC alpha kinase was prepared in assay buffer. To 16 μL of this enzyme buffer, in a 384 well plate, was added 1 μL of VRT stock solution in DMSO. The mixture was allowed to equilibrate for 10 mins at 30° C. The enzyme reaction was initiated by the addition of 16 μL stock ATP solution prepared in assay buffer to a final assay concentration of 130 μM. Initial rate data was determined from the rate of change of absorbance at 340 nM (corresponding to stoichiometric consumption of NADH) using a Molecular Devices Spectramax plate reader (Sunnyvale, Calif.) over 15 mins at 30° C. For each Ki determination 12 data points covering the VRT concentration range of 0-20 μM were obtained in duplicate (DMSO stocks were prepared from an initial 10 mM VRT stock with subsequent 1:2 serial dilutions). Ki values were calculated from initial rate data by non-linear regression using the Prism software package (Prism 4.0a, Graphpad Software, San Diego, Calif.).

B compounds are: 5, 7, 11, and 13. C compounds are: 2, 3, 4, 6, 8, and 10. C** compounds are: 1, 9, 12, 14, 15, 16, and 17.

While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds, methods, and processes of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example herein. 

1. A compound represented by structural formula I or IA:

or a pharmaceutically acceptable salt thereof wherein: each ring A is independently a five membered heteroaromatic ring, optionally substituted with one or more R₁; ring B is five- or six-membered saturated carbocyclic or heterocyclic ring; each R₁ is —H, halogen, —CN, —NO₂, or -T1-Q1; T1 is absent or a C1-10 aliphatic wherein one or more methylene units of T1 are optionally and independently replaced by G wherein G is —O—, —S(O)_(p)—, —N(R′)—, or —C(O)—; and T1 is optionally and independently substituted with one or more J_(T1); Q1 is absent or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, or an 8-12 membered saturated, partially saturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from the group consisting of O, N, and S, wherein Q1 is optionally and independently substituted with one or more J_(Q1); wherein when R₁ is T1-Q1, then T1 and Q1 are not both absent; R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)C(O)N(R*)₂, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, —(CR⁺⁺ ₂)_(n)N(R*)C(O)R*, or C1-10 aliphatic optionally substituted with one or more halogen, or phenyl; each R₃ and R₄ independently are —H, halogen, C1-10 aliphatic, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl, wherein R₃ and R₄ are optionally and independently substituted with one or more selected from the group consisting of C1-10 alkyl, halogen, —CN, —NO₂, —N(R*)₂, —S(O)_(p)R*, —S(O)_(p)NR*, —C(O)N(R)₂, —NR*C(O), —OC(O)N(R*)₂, —N(R*)C(O)OR*, —N(R*)C(O)N(R*)₂ and —OR*; or R₃ and R₄ taken together with the carbon to which they are attached form C═O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, ═N—R*, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —NO₂, —N(R*)₂, —S(O)_(p)R*, —S(O)_(p)NR*, —C(O)N(R*)₂, —NR*C(O), —OC(O)N(R*)₂, —N(R*)C(O)OR*, —N(R*)C(O)N(R*)₂ and —OR*; each R₅ and R₆ are independently —H, halogen, C1-10 haloaliphatic, or C1-10 aliphatic; each R₇ is independently C1-10 haloaliphatic, C1-10 aliphatic, halogen, —NO₂, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)N(R**)₂, —(CR⁺⁺ ₂)_(n)OR**, or —(CR⁺⁺ ₂)_(n)C(O)N(R**)₂, or two R₂ groups together with the carbon to which they are attached form C═O; each J_(T1) is independently halogen, —OR^(̂), —N(R^(̂))₂, or —CN; each J_(Q1) is independently halogen, C1-10 alkyl, C1-10 haloalkyl, —OR″, —N(R″)₂, —CN, —NO₂, —S(O)_(p)R″, —S(O)_(p)NR″, —C(O)N(R″)₂, —N(R″)C(O)R″, acyl, carbalkoxyalkyl, or acetoxyalkyl; each R⁺⁺is independently —H or halogen; each R′ is independently —H or C1-10 alkyl optionally and independently substituted with up to five halogen groups; each R^(̂) is independently —H, C1-10 alkyl, or aralkyl wherein each R^(̂) is optionally and independently substituted with up to five halogen groups; each R″ is independently —H or C1-10 alkyl optionally and independently substituted with up to five halogen groups; each R* is independently —H or C1-10 alkyl or aralkyl optionally and independently substituted with up to five halogen groups; each R^(**) is independently —H or C1-10 alkyl optionally and independently substituted with up to five halogen groups; y is 0, 1 or 2; each n is independently 0, or 1-10; and each p is independently 0, 1, or
 2. 2. The compound of claim 1 wherein the structural formula is represented by Formula I.
 3. The compound of claim 2 wherein: each R₁ is independently —H, halogen, or -T1-Q1.
 4. The compound of claim 3 wherein: T1 is absent or a C1-10 aliphatic wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —O—, —N(R′)—, or —C(O)—; and T1 is optionally and independently substituted with one or more J_(T1).
 5. The compound of claim 4 wherein: Q1 is absent or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein Q1 is optionally and independently substituted with one or more J_(Q1).
 6. The compound of claim 5 wherein: each J_(T1) is independently —OR^(̂), —N(R^(̂))₂, or —CN.
 7. The compound of claim 6 wherein: each J_(Q1) is independently C1-10 alkyl, —OR″, —N(R″)₂, or acyl.
 8. The compounds of claim 7 wherein: R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)C(O)N(R*)₂, —(CR⁺⁺ ₂).OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen.
 9. The compound of claim 8 wherein: each R₃ and R₄ independently is —H, C1-10 aliphatic, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl wherein R₃ and R₄ are optionally and independently substituted with one or more selected from the group consisting of halogen, —CN, —NO₂, —N(R*)₂, and —OR*; or R₃ and R₄ taken together with the carbon to which they are attached form C═O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)₂, and —OR*.
 10. The compound of claim 9 wherein: each R₃ and R₄ independently is —H, C1-10 aliphatic, cycloalkylalkyl, wherein R₃ and R₄ are optionally and independently substituted with one or more selected from the group consisting of halogen, —CN, —NO₂, —N(R*)₂, and —OR*; or R₃ and R₄ taken together with the carbon to which they are attached form C═O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)₂, and —OR*.
 11. The compound of claim 10 wherein: J_(T1) is —OR^(̂).
 12. The compounds of claim 11 wherein: R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen.
 13. The compound of claim 12 wherein: R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and R₃ and R₄ taken together with the carbon to which they are attached form a 3-8 membered saturated, or partially saturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)₂, and —OR*.
 14. The compound of claim 13 wherein: R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and R₃ and R₄ taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, imidazolinyl, thiazolidinyl, or oxazolidinyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)₂, and —OR*.
 15. The compound of claim 14 wherein: R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and R₃ and R₄ taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, imidazolinyl, thiazolidinyl, or oxazolidinyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)₂, and —OR*.
 16. The compound of claim 14 wherein: R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and R₃ and R₄ taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, or cyclopentyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)₂, and —OR*.
 17. The compounds of claim 14 wherein: R₂ is —H, —(CR⁺⁺ ₂)_(n)CN, —(CR⁺⁺ ₂)_(n)OR*, —(CR⁺⁺ ₂)_(n)N(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and each R₃ and R₄ independently is —H, C1-10 aliphatic, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl wherein R₃ and R₄ are optionally and independently substituted with one or more selected from the group consisting of halogen, —CN, —NO₂, —N(R*)₂, and —OR*.
 18. The compounds of claim 17 wherein R₅ is —H, Cl, C1-4 haloalkyl, or C1-4 alkyl; and R₆ is —H or C1-4 alkyl.
 19. The compounds of claim 18 wherein R₅ is —H, Cl, trifluoromethyl, methyl, ethyl, or cyclopropyl; and R₆ is —H.
 20. The compounds of claim 18 wherein R₅ is trifluoromethyl; and R₆ is —H.
 21. The compound of claim 1 wherein the structural formula is represented by Formula IA.
 22. The compound of claim 21 wherein: each R₁ is independently —H, halogen, or -T1-Q1.
 23. The compound of claim 22 wherein: T1 is absent or a C1-10 aliphatic wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —O—, —N(R′)—, or —C(O)—; and T1 is optionally and independently substituted with one or more J_(T1).
 24. The compound of claim 23 wherein: Q1 is absent or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein Q1 is optionally and independently substituted with one or more J_(Q1).
 25. The compound of claim 24 wherein: each J_(T1) is independently —OR^(̂), —N(R^(̂))₂, or —CN.
 26. The compound of claim 25 wherein: each J_(Q1) is independently C1-10 alkyl, —OR″, —N(R″)₂, or acyl.
 27. The compounds of claim 26 wherein R₅ is —H, Cl, C1-4 haloalkyl, or C1-4 alkyl; and R₆ is —H or C1-4 alkyl.
 28. The compounds of claim 27 wherein R₅ is —H, Cl, trifluoromethyl, methyl, ethyl, or cyclopropyl; and R₆ is —H.
 29. The compounds of claim 28 wherein R₅ is trifluoromethyl; and R₆ is —H.
 30. The compound of claim 29 wherein: ring B is five- or six-membered saturated carbocyclic ring.
 31. The compound of claim 30 wherein: each R₇ is independently C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R)₂, or —OR**; or two R₇ groups together with the carbon to which they are attached form C═O.
 32. The compound of claim 31 wherein: A is —C(R⁺)—.
 33. The compound of claim 32 wherein: J_(T1) is —OR^(̂).
 34. The compound of claim 33 wherein: each J_(Q1) is independently C1-10 alkyl, —OR″, —N(R″)₂, or acyl.
 35. The compound of claim 24 wherein: ring B is five-membered saturated carbocyclic ring.
 36. A compound represented by a structural formula selected from Table 1, or a pharmaceutically acceptable salt thereof.
 37. A composition comprising a compound or pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
 38. A method of treating or preventing a protein kinase-mediated condition in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 1 or pharmaceutically acceptable salt thereof.
 39. The method of claim 38, wherein the protein kinase-mediated condition is a PKC mediated condition.
 40. The method of claim 39, wherein the PKC-mediated condition is a PKCtheta mediated condition.
 41. The method of claim 40, wherein the PKCtheta mediated condition is an autoimmune disease, an inflammatory disease or a proliferative or hyperproliferative disease.
 42. The method of claim 40, wherein the PKCtheta mediated condition is selected from the group consisting of asthma, psoriasis, arthritis, rheumatoid arthritis, joint inflammation, multiple sclerosis, diabetes, inflammatory bowel disease, transplant rejection, T-cell leukaemias, lymphomas, and lupus.
 43. The method of claim 41, wherein the PKCtheta mediated condition is an autoimmune disease.
 44. The method of claim 41, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, irritable bowel disease
 45. The method of claim 41, wherein the autoimmune disease is multiple sclerosis.
 46. The method of claim 41, wherein the autoimmune disease is rheumatoid arthritis.
 47. The method of claim 41, wherein the autoimmune disease is irritable bowel disease.
 48. The method of claim 40, wherein the PKCtheta mediated condition is selected from the group consisting of T-cell leukaemia and lymphoma. 